Abstract 4561: 3D Reconstructed Pancreas: A model capturing the unique tumor microenvironment and stromal architecture of pancreatic cancer
Authors: Arnat Balabyev, Justin D. Phillips, Michael Steffey, Eleanore J. Kirshner, Aayushi Ahlawat, Arlette H. Uihlein, Daniel Saims, Scott Wise, Julia Kirshner
Journal: Cancer Research (2023)

Abstract As it is rarely discovered early, the prognosis for people with pancreatic cancer is poor, with an average 5-year survival rate of 10% and only 3% for those with metastatic illness. Pancreatic cancer patients have few therapeutic options and innovative therapies are sorely needed to improve treatment of the disease. This is mainly due to the late diagnosis and partially due to the biology of the disease. Capturing the components of the tumor microenvironment, which serve as both a physical barrier and a source of stromal-driven resistance to therapeutics, is one of the issues faced by drug developers searching for agents to combat pancreatic cancer. We have created a 3D model of the pancreatic tumor microenvironment, the Reconstructed Pancreas (r-Pancreas), using Mia PaCa-2, PANC-1, and BxPC-3 pancreatic tumor cell lines embedded in an extracellular matrix (ECM) that was formulated to recapitulate the typical ECM of pancreatic tumors. We have shown that gemcitabine was effective against pancreatic tumor cells cultured in r-Pancreas (IC50=0.4-0.8µM), while 5-fluorouracil was ineffective (IC50 not reached), mimicking clinical response. In nude mice, subcutaneous PANC-1 tumors exhibited similar responses to gemcitabine and 5-fluorocurcil. Treatment with gemcitabine resulted in a Day 63 median ΔT/ΔC of 37% while 5-fluorouracil resulted in a Day 63 median delta ΔT/ΔC of 102%. Incorporating a collagen-rich capsule increases the physiological relevance of the r-Pancreas model because it has been shown that human pancreatic tumors have an outer layer of stiff ECM that functions as a physical barrier and prevents drugs from penetrating the tumor. Recently, we showed that, at least in the Mia PaCa-2 and BxPC-3 tumor cell lines, introducing such a collagen capsule dramatically reduced sensitivity to gemcitabine. Disrupting the collagen capsule with MMP-9 restored the sensitivity of the tumor cells to gemcitabine demonstrating that the capsule provides a physical barrier to drug entry. Additionally, creating a co-culture of primary activated pancreatic stromal cells and pancreatic tumor cell lines produces a more complete 3D model that permits the testing of potential therapeutic agents inside the pancreatic tumor microenvironment. Hence, we have created a 3D model where pancreatic tumor cells were co-cultured with human pancreatic fibroblasts. According to our results, the IC50 values for pancreatic tumor cell lines treated with gemcitabine increased by twofold when co-cultured with activated pancreatic fibroblasts compared to control sets of tumor cells alone (IC50=1-3µM). Together, these data imply that, to be clinically relevant, in vitro models of pancreatic cancer must integrate tumor-specific components of the microenvironment, including the collagen capsule and activated fibroblasts. Citation Format: Arnat Balabyev, Justin D. Phillips, Michael Steffey, Eleanore J. Kirshner, Aayushi Ahlawat, Arlette H. Uihlein, Daniel Saims, Scott Wise, Julia Kirshner. 3D Reconstructed Pancreas: A model capturing the unique tumor microenvironment and stromal architecture of pancreatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4561.